Nuclear Receptors

Nuclear Receptors
Unlike peptide hormones and epinephrine,
which are much too large to
pass through cell membranes, steroid
hormones (for example, estrogen,
testosterone, and aldosterone), are
lipid-soluble molecules that readily diffuse
through cell membranes. Once
inside the cytoplasm, steroid hormones bind selectively to receptor molecules
of target cells. While these receptor
molecules may be located in either
cytoplasm or nucleus, their ultimate
site of activity is the nucleus. The
hormone-receptor complex, now
known as a gene regulatory protein, then activates or inhibits specific genes.
As a result, gene transcription is altered,
since messenger RNA molecules
are synthesized on specific sequences
of DNA. Stimulation or inhibition of
mRNA formation modifies production
of key enzymes, thus setting in motion
the hormone’s observed effect (Figure
36-2). Thyroid hormones and the
insect-molting hormone, ecdysone, also
act through nuclear receptors.

Figure 36-2 Mechanisms of hormone action. Peptide hormones and
epinephrine
act
through second messenger
systems, as for example,
cyclic AMP, shown here.
The combination of hormone with a membrane
receptor stimulates the enzyme adenylate
cyclase to catalyze formation
of cyclic AMP (second
messenger). Steroid hormones
and thyroid
hormones penetrate the cell membrane to combine with
cytoplasmic
or nuclear receptors that alter gene transcription.

Compared with peptide hormones
that act indirectly through second messenger
systems, steroids have a direct
effect on protein synthesis because
they bind a nuclear receptor that modifies
specific gene activity.

Control of Secretion Rates
of Hormones
Hormones influence cellular functions
by altering rates of many different biochemical
processes. Many affect enzymatic
activity and thus alter cellular
metabolism, some change membrane
permeability, some regulate synthesis of
cellular proteins, and some stimulate
release of hormones from other endocrine
glands. Because these are all dynamic
processes that must adapt to
changing metabolic demands, they must
be regulated, not merely activated, by
the appropriate hormones. This regulation
is achieved by precisely controlled
release of a hormone into the blood.
However, the concentration of a hormone
in the plasma depends on two
factors: its rate of secretion and the rate
at which it is inactivated and removed
from the circulation. Consequently, if
secretion is to be correctly controlled, an
endocrine gland requires information about the level of its own hormone(s) in
the plasma.

Figure 36-3 Negative feedback systems.

Many hormones are controlled by
negative feedback systems that operate
between glands secreting the hormones
and target cells (Figure 36-3). A feedback
pattern is one in which output is
constantly compared with a set point,
like a thermostat. For example, CRH
(corticotropin-releasing hormone),
secreted by the hypothalamus, stimulates
the pituitary (the target cells) to
release ACTH. ACTH stimulates the
adrenal gland (the target cells) to
secrete cortisol. As the level of ACTH
rises in the plasma, it acts on, or “feeds
back” on, the hypothalamus to inhibit
release of CRH. Similarly, as cortisol levels
rise in the plasma, it “feeds back” on
the hypothalamus and pituitary to
inhibit release of both CRH and ACTH,
respectively. Thus any deviation from
the set point (a specific plasma level of
each hormone) leads to corrective
action in the opposite direction (Figure
36-3). Such a negative feedback system is highly effective in preventing
extreme oscillations in hormonal output.
However, hormonal feedback systems
are more complex than a rigid
“closed-loop” system such as the thermostat
that controls the central heating
system in a house, because hormonal
feedback may be altered by input from
the nervous system or by metabolites or
other hormones.

Figure 36-4 Endocrine control of molting in a moth, typical of insects having complete metamorphosis.
Many moths mate in spring or summer,
and eggs soon hatch
into the first of several larval stages, called instars.
After the final larval molt, the last and largest larva (caterpillar)
spins a cocoon in which it pupates.
The
pupa overwinters, and an adult emerges in the spring to start a new generation. Juvenile hormone
and ecdysone interact to control molting and pupation.
Many genes are activated during metamorphosis,
as seen by puffing of
chromosomes (center column). Puffs form in sequence during successive molts.
Changes in cuticle thickness and surface characteristics
are shown at right.

Extreme oscillations in hormone
output do sometimes occur under natural
conditions. However, because
they have the potential to disrupt
finely tuned homeostatic mechanisms,
such extreme oscillations, as a result of positive feedback, are highly regulated
and possess an obvious shutoff
mechanism. For example, hormones
controlling parturition (childbirth) are
shut off by birth of the young from the
uterus; hormones controlling ovulation
are shut off by release of an ovum
from a follicle.